TY - JOUR
T1 - Valproate activates bovine leukemia virus gene expression, triggers apoptosis, and induces leukemia/lymphoma regression in vivo.
AU - Achachi, A.
AU - Florins, A.-F.
AU - Gillet, N.
AU - DEBACQ, Christophe
AU - Urbain, Jean-Pierre
AU - Foutsop, G. M.
AU - VANDERMEERS, Fabian
AU - Jasik, A.
AU - Reichert, M.
AU - Kerkhofs, P.
AU - Lagneaux, L.
AU - Burny, Arsène
AU - Kettmann, R
AU - Willems, L.
PY - 2005
Y1 - 2005
N2 - [en] Leukemogenic viruses like human T-lymphotropic virus and bovine leukemia virus (BLV) presumably persist in the host partly by latent integration of the provirus in a fraction of infected cells, leading to accumulative increase in the outgrowth of transformed cells. Furthermore, viral infection also correlates with a blockade of the apoptotic mechanisms concomitant with an apparent latency of the host cell. Conceptually, induction of viral or cellular gene expression could thus also be used as a therapeutic strategy against retroviral-associated leukemia. Here, we provide evidence that valproate, an inhibitor of deacetylases, activates BLV gene expression in transient transfection experiments and in short-term cultures of primary B-lymphocytes. In vivo, valproate injection into newly BLV-inoculated sheep did not abrogate primary infection. However, valproate treatment, in the absence of any other cytotoxic drug, was efficient for leukemia/lymphoma therapy in the sheep model leading to decreased lymphocyte numbers (respectively from 25.6, 35.7, and 46.5 x 10(3) cells per mm3 to 1.0, 10.6, and 24.3 x 10(3) cells per mm3 in three leukemic sheep) and tumor regression (from >700 cm3 to undetectable). The concept of a therapy that targets the expression of viral and cellular genes might be a promising treatment of adult T cell leukemia or tropical spastic paraparesis/human T-lymphotropic virus-associated myelopathy, diseases for which no satisfactory treatment exists so far.
AB - [en] Leukemogenic viruses like human T-lymphotropic virus and bovine leukemia virus (BLV) presumably persist in the host partly by latent integration of the provirus in a fraction of infected cells, leading to accumulative increase in the outgrowth of transformed cells. Furthermore, viral infection also correlates with a blockade of the apoptotic mechanisms concomitant with an apparent latency of the host cell. Conceptually, induction of viral or cellular gene expression could thus also be used as a therapeutic strategy against retroviral-associated leukemia. Here, we provide evidence that valproate, an inhibitor of deacetylases, activates BLV gene expression in transient transfection experiments and in short-term cultures of primary B-lymphocytes. In vivo, valproate injection into newly BLV-inoculated sheep did not abrogate primary infection. However, valproate treatment, in the absence of any other cytotoxic drug, was efficient for leukemia/lymphoma therapy in the sheep model leading to decreased lymphocyte numbers (respectively from 25.6, 35.7, and 46.5 x 10(3) cells per mm3 to 1.0, 10.6, and 24.3 x 10(3) cells per mm3 in three leukemic sheep) and tumor regression (from >700 cm3 to undetectable). The concept of a therapy that targets the expression of viral and cellular genes might be a promising treatment of adult T cell leukemia or tropical spastic paraparesis/human T-lymphotropic virus-associated myelopathy, diseases for which no satisfactory treatment exists so far.
KW - Sciences de la santé humaine => Oncologie
KW - Animals
KW - Apoptosis/drug effects
KW - B-Lymphocytes/metabolism
KW - Enzyme-Linked Immunosorbent Assay
KW - Flow Cytometry
KW - Gene Expression Regulation, Viral/drug effects
KW - Hela Cells
KW - Histone Deacetylases/antagonists inhibitors
KW - Humans
KW - Leukemia Virus, Bovine/metabolism
KW - Leukemia, Lymphoid/therapy
KW - Leukocytes, Mononuclear/metabolism
KW - Luciferases
KW - Lymphocyte Count
KW - Proviruses/metabolism
KW - Remission Induction
KW - Sheep
KW - Valproic Acid/pharmacology/therapeutic use
U2 - 10.1073/pnas.0504248102
DO - 10.1073/pnas.0504248102
M3 - Article
SN - 0027-8424
VL - 102
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 29
ER -